EDITOR'S PICK: With or without you: premature ageing whether or not protein is modified
Hutchinson-Gilford progeria syndrome (HGPS) is a rare childhood disease that resembles premature aging, and few affected children reach their teenage years. It is caused by a mutation in the LMNA gene that leads to the formation of progerin — a mutant form of the protein prelamin A. Once made, both progerin and normal prelamin A have the molecule farnesyl attached to them. This addition is later removed from normal prelamin A, whereas it cannot be removed from progerin. It has been suggested that farnesylated progerin is important for the development of disease in individuals with HGPS, and inhibitors of farnesylation are currently being evaluated in clinical trials. However, new data, generated by Stephen Young, Loren Fong, and colleagues, at the UCLA David Geffen School of Medicine, Los Angeles, in a new mouse model of HGPS suggest that inhibitors of farnesylation are likely to have limited therapeutic success as both farnesylated and nonfarnesylated progerin can cause symptoms of disease.
TITLE: Progerin elicits disease phenotypes of progeria in mice whether or not it is farnesylated
AUTHOR CONTACT:
Stephen G. Young
UCLA David Geffen School of Medicine, Los Angeles, California, USA.
Phone: (310) 825-4934; Fax: (310) 206-0865; E-mail: sgyoung@mednet.ucla.edu.
Loren G. Fong
UCLA David Geffen School of Medicine, Los Angeles, California, USA.
Phone: (310) 825-4934; Fax: (310) 206-0865; E-mail: lfong@mednet.ucla.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35876
EDITOR'S PICK: Stem cell transplantation benefits mice with childhood motor neuron disease
The motor neuron disease spinal muscular atrophy (SMA) is the second most common genetic disorder leading to death in childhood. There is currently no cure for SMA, but some clinicians and researchers consider stem cell transplantation as a potential therapeutic strategy. And now, Giacomo Comi and colleagues, at the University of Milan, Italy, have generated data using a mouse model of SMA to suggest that spinal cord neural stem cells (NSCs) might be a possible treatment for individuals with SMA.
In the study, NSCs from mice in which a green marker protein was expressed only in nerve cells known as motor neurons (the cells that are defective in SMA) were transplanted into the fluid bathing the spinal cord of mice with an SMA-like disease. The transplanted cells developed into a small number of motor neurons and the treated mice showed improved muscular function and increased lifespan, when compared with untreated mice. Further analysis indicated that the major effect of NSC transplantation was that the transplanted cells improved the survival and function of the motor neurons already in the mice, making them more like normal motor neurons (at the gene expression level). The authors therefore suggest that in the future, NSCs might be used in the development of therapeutic protocols for the treatment of SMA and other motor neuron diseases.
TITLE: Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy
AUTHOR CONTACT:
Giacomo P. Comi
University of Milan, Milan, Italy.
Phone: 390255033817; Fax: 390250320430; E-mail: giacomo.comi@unimi.it.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35432
EDITOR'S PICK: How to spot a heart attack soon after it occurs
The sooner an individual who has had a heart attack is treated, the better their chance of survival and the less permanent damage is done to their heart. So, Robert Gerszten and colleagues, at Massachusetts General Hospital, Charlestown, have developed a new method for early detection of a heart attack.
In the study, blood samples were collected before and after a number of patients with the heart condition hypertrophic cardiomyopathy were treated using a medical procedure that creates a small controlled heart attack. These samples were then analyzed by a method known as metabolite profiling. Changes in a number of metabolites were observed only 10 minutes after the planned heart attack. This same signature of changes was observed in a second series of patients undergoing the same procedure and in a number of patients spontaneously having a heart attack. The authors believe that no other method can detect changes indicating a heart attack so soon after it has occurred, and hope that their approach can be used to improve early detection of a heart attack.
TITLE: Metabolite profiling of blood from individuals undergoing planned myocardial infarction reveals early markers of myocardial injury
AUTHOR CONTACT:
Robert E. Gerszten
Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Phone: (617) 724-8322; Fax: (617) 726-1544; E-mail: rgerszten@partners.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35111
AUTOIMMUNITY: Regulatory immune cells not defective in multiple sclerosis
Multiple sclerosis (MS) is a chronic inflammatory disease that causes neurodegeneration, resulting in numerous physical and mental disabilities. It is thought to be caused by out of control immune cells that attack the proteins that make up the protective sheath in which nerve cells are encased. In addition, it has been reported that a subset of immune cells known as Tregs (characterized by expression of the protein CD4 and high levels of expression of the protein CD25), which suppresses the function of aggressive immune cells, is defective in individuals with MS, and that this contributes to the progression of the disease. However, it has recently been shown that if CD4+CD25high cells are divided into cells expressing high and low levels of the protein CD127 only the CD4+CD25highCD127low cells have suppressive capability. Thus, Jean-Paul Soulillou and colleagues, at INSERM U643, France, compared the suppressive capabilities of CD4+CD25highCD127low cells from individuals with MS and healthy individuals. Surprisingly, they found that these cell populations were equally effective suppressors of aggressive immune cells when analyzed in vitro. These data therefore indicate that the suppressive function of Tregs (when characterized as CD4+CD25highCD127low) is not defective in individuals with MS, suggesting that this defective Treg function is not a factor that contributes to the development of this debilitating autoimmune disease.
TITLE: Patients with relapsing-remitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor alpha-chain are excluded from the analysis
AUTHOR CONTACT:
Jean-Paul Soulillou
INSERM U643, Nantes, France.
Phone: 33-2-40-08-74-10; Fax: 33-2-40-08-74-11; E-mail: Jean-Paul.Soulillou@univ-nantes.fr.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35365
VIROLOGY: How does herpes simplex virus cause inflammation of the brain? By exploiting the cellular protein Egr1
Worldwide, about 80% of young adults are infected with herpes simplex virus type 1 (HSV-1). The most common symptom of infection is a cold sore, but in some individuals the virus can also cause life-threatening inflammation of the brain (encephalitis); 70% of individuals who do not get treatment for this condition die. New insight into the cellular proteins that the virus exploits to replicate itself and cause death from encephalitis has now been provided by a team of researchers at the National Cheng Kung University and the National Chiayi University, in the Republic of China, who analyzed human cell lines and mice infected with HSV-1.
In the study, expression of a cellular protein known as Egr1 was found to be increased after a human nerve cell line was infected with HSV-1. Further, Egr1 was shown to increase replication of the virus. Increased expression of Egr1 was also observed in the brain of mice infected with HSV-1. Importantly, two different approaches to decrease Egr1 expression in the brain reduced the number of mice that died as a result of HSV-1 encephalitis, and this was associated with decreased numbers of viruses in the mice. The authors therefore suggest that these data provide rationale for further studies to test whether blocking Egr1 could be a new strategy for preventing HSV-1–induced encephalitis and other conditions.
TITLE: Suppression of transcription factor early growth response 1 reduces herpes simplex virus lethality in mice
AUTHOR CONTACT:
Shun-Hua Cehn
National Cheng Kung University, Tainan, Taiwan, Republic of China.
Phone: 886-6-2353535 ext, 5633; Fax: 886-6-2082705; Email: shunhua@mail.ncku.edu.tw.
Ching Li
National Chiayi University, Chiayi, Taiwan, Republic of China.
Phone: 886-5-2717833; Fax: 886-5-2717831; E-mail: chingli@mail.ncyu.edu.tw.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35114
METABOLIC DISEASE: Opposites attract: the protein apelin counters the effects of Ang II in diseases of the major arterial blood vessels
One of the most common causes of death in the developed world is a disease of the major arterial blood vessels that can cause heart attacks and stroke. New insight into the molecular pathways involved in this disease (which is known as atherosclerosis, or hardening of the arteries) and another disease of the main arterial blood vessel leaving the heart (abdominal aortic aneurysm [AAA]) has been provided by Thomas Quertermous and colleagues, at Stanford University School of Medicine, who studied a mouse model of these diseases — the ApoE-KO mouse.
In the study, administration of the hormone Ang II to ApoE-KO mice induced atherosclerosis and the formation of AAA. The effects of Ang II could be inhibited by coinfusion of another natural molecule, apelin. Further analysis indicated that apelin inhibited the effects of Ang II by increasing production of a molecule known as NO and by blocking Ang II–initiated signaling (in part through the interaction of the receptor for apelin and the receptor for Ang II). These data identify a mechanism whereby the ability of Ang II to cause diseases of the major arterial blood vessels can be countered, information that is likely to be of interest to those developing therapeutics for these diseases.
TITLE: Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis
AUTHOR CONTACT:
Thomas Quertermous
Stanford University School of Medicine, Stanford, California, USA.
Phone: (650) 723-5013; Fax: (650) 725-2178; E-mail: tomq1@stanford.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34871
Journal
Journal of Clinical Investigation